Treatment of viral infections using levovirin

ABSTRACT

A 1-(β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide is administered in a method of treatment of a viral infection in a patient, including IV infection, HCV infection, or BHV infection.

[0001] This application claims the benefit of U.S. patent applicationSer. No. 09/471,513 filed Dec. 23, 1999 which claims the benefit of U.S.provisional applications Nos. 60/164,366 and 60/164,365, all of whichare incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The field of the invention is treatment of viral infections.

BACKGROUND OF THE INVENTION

[0003] Many viral infections are associated with a shift in the cytokineprofile from a Th1 response to Th2 response, and recent researchsuggests that a control over the balance between the Th1 response andthe Th2 response might be advantageous in terms of generation and/ormaintenance of immunity against viral infection. An increased Th1response appears to be especially important in HIV infection, wherelong-term survivors exhibit a Th1 dominated response, while progressorshave a more Th2 dominated response. For example. Barker et al. suggestthat disease progression in HIV results from a shift in cytokineproduction within the infected host from a Th1 to a Th2 pattern [BarkerE. Mackewicz C E, Levy J A Proc Natl Acad Sci U S A Nov. 21,1195;92(24): 11135-9]. Similarly, a decrease in the Th2 response appearsto be of therapeutic significance, since Reiser et al. report that Th2cytokine levels are elevated in chronic hepatitis C virus infection[Reiser, M. et al.: J Hepatol March 1997;26(3):471-8]. Various methodsof influencing the Th1/Th2 balance are known, and may broadly becategorized in cytokine-related methods and non-cytokine relatedmethods.

[0004] In cytokine related methods of treatment, cytokines areadministered to modulate the Th1/Th2 balance towards either a Th1-typeresponse or a Th2-type response. For example, Knight et al. postulatethat treatment with IL-12 (Interleukine-12), a cytokine that promotesthe development of Th1 cells, may be used as a treatment for AIDS sinceIL-12 administration has been shown to be effective at restoringcell-mediated immunity in mice infected with mouse AIDS virus or withRauscher Leukemia Virus (RLV) [Knight, S. C. and Patterson. S., Annu.Rev. Immunol. 1994, 15: 593-615]. In another example, Gracie, J A. etal, demonstrated that administration of IL-18 to mice exhibitedpleiotropic activities critical to the development of Th1 responses.[Gracie et al. J Clin Invest Nov. 15, 1999;104(10):1393-1401]. Althoughthe administration of cytokines typically results in relatively specificincreases in desired Th1 cytokines, prolonged administration ofcytokines may be problematic for various reasons. For example, theproduction of recombinant cytokines is relatively expensive, andisolation of non-recombinant cytokines from natural sources is generallydifficult due to the very low concentration of cytokines in naturalsources. A further problem is that cytokine preparations typically needto have a very high degree of purity in order to avoid allergicreactions upon repeated administration. Moreover, depending on thenature of the cytokine, cytokines may not be well tolerated in patients.

[0005] In a non-cytokine related method, immuno-modulatory substancesother than cytokines are employed to modulate the balance between a Th1response and a Th2 response. For example, Sprietsma J. E. suggests[Sprietsma J. E; Med Hypotheses July 1999;53 (1):6-16] that zinc ions(Zn⁺⁺) and nitric oxide (NO), together with glutathione (GSH) and itsoxidized form. GSSG, may help to regulate an immune response toantigens. The author reports in more detail that deficiencies of Zn⁺⁺.NO and/or GSH shift the Th1/Th2 balance towards Th2, and thatreplenishment with Zn⁺⁺, NO and/or GSH may shift the Th1/Th2 balancetowards Th1. Administration of Zn⁺⁺ or GSH/GSSG is especiallyadvantageous, since these substances are non-toxic at even elevatedconcentrations, and inexpensive to produce. Furthermore. Zn⁺⁺ andGSH/GSSG preparations may be orally administered, and thereforesignificantly reduce the risk of allergic reactions, especially when thepreparations are not ultrapure. However, the administration of Zn⁺⁺and/or GSH/GSSG seems to be beneficial only to restore a Th1/Th2 balancefrom a Th2 dominated state, whereas it is unclear if administration ofZn⁺⁺ and/or GSH/GSSG may increase a Th1 response from a normal Th1/Th2balance.

[0006] In another example, U.S. patent application Ser. No. 09/156,646incorporated herein by reference, a method is described in which theinventors employ the nucleoside analog Ribavirin(1-(5-Deoxy-β-D)-ribofuranosyl)-1,2,4-triazole-3-carboxamide) tomodulate the balance of the Th1/Th2 response. The use of Ribavirin isespecially advantageous for the treatment of viral infections, becauseRibavirin not only modulates the immune response towards a Th1 response,but also acts as an inhibitory agent for viral replication. For example,Ribavirin has been successfully used in the treatment of Hepatitis C.Some of this effect has been attributed to antiviral effects and some ofthis effect has been attributed to the cytokine balance.

[0007] Although Ribavirin showed a desirable effect in virus count andimmune status, prolonged administration of Ribavirin at relatively highdoses was frequently associated with several side effects, includingleukopenia and hemolytic anemia. In order to reduce the occurrence orseverity of side effects, co-administration of Ribavirin with IFNα-2Bhas been introduced [Reichert, O., et al.1998; Lancet 351:83-87].However, the co-administration of Ribavirin with IFNα-2B increases thecost of treatment significantly. Moreover, prolonged administration ofIFNα-2B increases the risk of new side effects attributable to IFNα-2B.

[0008] Despite the relatively successful administration of Ribavirin inthe treatment of viral diseases, the use of Ribavirin remainsproblematic due to the generation of various side effects. Therefore,there is a need to provide improved methods and compositions to modulatethe Th1/Th2 balance at a relatively low or no toxic side effects fortreatment of viral infections.

SUMMARY OF THE INVENTION

[0009] The present invention is directed to a method of treatment of aviral infection in a patient, in which Levovirin™(1-(β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide) is administered tothe patient, and wherein the viral infection is an HIV infection, a HCVinfection, or a HBV infection.

[0010] In one aspect of the inventive subject matter, the administrationof the Levovirin™ increases the Th1 response relative to the Th2response in the patient, and it is especially contemplated that the Th1response increases on an absolute. In further aspects of the inventivesubject matter, Levovirin™ is administered in vivo, preferably injectedi.v., or orally taken, wherein the preferred dose of Levovirin™ isbetween 0.1 mg/kg and 1.0 mg/kg.

[0011] Various objects, features aspects and advantages of the presentinvention will become more apparent from the following detaileddescription of preferred embodiments of the invention along with theaccompanying drawings in which like numerals represent like components.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a structure of Levovirin™.

[0013]FIG. 2 is a synthetic scheme for the synthesis of Levovirin™.

[0014] FIGS. 3A-C are graphs depicting various biological effects ofLevovirin™ and Ribavirin on elements of the Th1 response.

[0015]FIG. 4 is a graph showing serum ALT levels in Con A injected micedependence of treatment with Levovirin™ and Ribavirin.

DETAILED DESCRIPTION

[0016] As used herein, the term “viral infection” refers to any stage ofa viral infection, including incubation phase, latent or dormant phase,acute phase, and development and maintenance of immunity towards avirus. Consequently, the term ‘treatment’ is meant to include aspects ofgenerating or restoring immunity of the patient's immune system, as wellas aspects of suppressing or inhibiting viral replication.

[0017] As also used herein, lymphokines are a subset of cytokinesproduced by helper T cells, and are generally considered to fall intotwo subclasses. Th1 and Th2. Th1 cells (more modernly known as Type Icells) produce interleukin 2 (IL-9), tumor necrosis factor (TNFα) andinterferon gamma (IFNγ), and are responsible primarily for cell-mediatedimmunity such as delayed type hypersensitivity and antiviral immunity.In contrast. Th2 cells (more modernly known as Type 2 cells) produceinterleukins, IL4, IL-5, IL-6, IL-9, IL-10 and IL-13, and are primarilyinvolved in assisting humoral immune responses such as those seen inresponse to allergens, e.g. IgE and IgG4 antibody isotype switching(Mosmann, 1989, Annu Rev Immunol, 7:145-173).

[0018] As further used herein, the terms Th1 and Th2 “responses” aremeant to include the entire range of effects resulting from induction ofTh1 and Th2 lymphocytes, respectively. Among other things, suchresponses include increased production of the corresponding cytokines,increased proliferation of the corresponding lymphocytes, and othereffects associated with increased production of cytokines, includingmotility effects. A Th1 response is generally characterized by anincrease in IL-2, TNF-α, and IFN-γ, whereas a Th2 response is typicallycharacterized by an increase in IL4, IL-5, IL-6, and IL-10.

[0019] In a preferred embodiment, an HIV infected patient with a CD4lymphocyte count of about 500 cells per microliter receives once dailyover a period of 30 days a single injection of an aqueous solution ofLevovirin™ in a total dose of 0.5 mg/kg body weight.

[0020] In alternative aspects of the inventive subject matter, the HIVinfection need not be limited to a CD4 lymphocyte count of about 500cells per microliter, but may also include lower CD4 lymphocyte counts,including CD4 lymphocyte counts between 500 and 300, 300-150, and lessthan 150. Similarly, higher CD4 lymphocyte counts (i.e.>500) are alsocontemplated. It should further be appreciated that various clinicalmarkers other than virus titer and CD4 lymphocyte count may beappropriate, including direct and indirect assays for the presence ofthe HIV virus. For example, direct assays are quantitative culture ofPBMCs and plasma HIV, qualitative and quantitative PCR methods and soforth. Indirect assays include qualitative and quantitative ELISAmethods, etc.

[0021] With respect to the virus type of the viral infection it iscontemplated that the treatment of the viral infection is not limited toa specific type or subtype of HIV virus, and it should be appreciatedthat various viruses other than a HIV are also contemplated. It isgenerally contemplated that alternative virus infections include virusinfections that can be treated with Ribavirin, which is the D-isomer ofLevovirin™ Especially contemplated alternative viral infections includeHCV infection, and HBV infection.

[0022] In further alternative aspects of the inventive subject matter,the administration of Levovirin™ need not be restricted to a singledaily injection over a period of 30 days, but may include alternativefrequencies and routes. For example, where relatively high amounts ofLevovirin™ need to be delivered, two to four or more daily injectionsare contemplated. Similarly, where high plasma concentrations ofLevovirin™ are desired over an extended period, a permanent delivery iscontemplated. For example, a more permanent delivery may include the useof a continuous infusion, an osmotic pump, or a sustained releaseimplant. It should further be appreciated that the delivery route is notlimited to injections, but appropriate delivery may include oraldelivery, transdermal delivery, intranasal delivery pulmonary delivery,etc. Consequently, the formulation of alternative Levovirin™preparations may include tablets, syrups, gels, aerosols, and so forth.It is further contemplated that the administration of Levovirin™ mayalso be in vitro. For example, a predetermined quantity of whole bloodor fractions of whole blood may be pre-incubated with Levovirin™ invitro to either boost or generate an immune reaction towards animmunogenic challenge.

[0023] With respect to the dosage of Levovirin™, it is contemplated thatvarious alternative dosages are also appropriate, including dosagesbetween 0.5 mg/kg and 0.1 mg/kg and less, but also dosages between 0.5and 11.0 mg/kg and more. In general, the appropriate dosage will dependon multiple parameters, including the type of virus infection, the stageof the virus infection, the desired plasma concentration of Levovirin™,the duration of the treatment, etc. For example, while treatment successmay be achieved with some viral infections at relatively low plasmaconcentrations of Levovirin™, other viral infections may requirerelatively high dosages.

[0024] In still further alternative aspects of the inventive subjectmatter. Levovirin™ may be combined with additional pharmaceuticallyactive substances to assist in the treatment of the viral infections.Contemplated additional pharmaceutically active substances includeantiviral agents and immune modulator substances. For example, antiviralagents are protease inhibitors, or nucleotide and nucleoside analogs,and immune modulator substances may include cytokines.

[0025] Although not wishing to be bound to any particular theory, it iscontemplated that the administration of Levovirin™ is correlated with anincrease of the Th1 response relative to the Th2 response in a patient,and it is especially contemplated that the relative increase of the Th1response to the Th2 response is due to an absolute increase in the Th1response. The cytokine levels may thereby be increased individually orcollectively. For example, it is contemplated that administration ofLevovirin™ to activated human PBMCs may result in a mean peak increaseof the IL-2 level of at least 70%(by weight) over an activated controllevel. Alternatively, it is contemplated that administration ofLevovirin™ to activated human PBMCs may result in a mean peak increaseof the IFN-γ level of at least 20% (by weight) over an activated controllevel, or in a mean peak increase of the TNF-α level of at least 50% (byweight) over an activated control level (see also FIGS. 3A-C). Inanother example, it is contemplated that the increase in the Th1response may comprises a mean peak increase over an activated controllevel in IL-2, IFN-γ, and TNF-α of 42% (by weight), 125% (by weight),and 72% (by weight), respectively.

[0026] It should especially be appreciated that while the spectrum oftreatable viral infections is somewhat overlapping between Ribavirin andLevovirin™, Levovirin™ has a substantially reduced toxicity. Forexample, while oral administration of Ribavirin in rats at 180 mg/kgover four weeks produced significant hemolytic anemia and leukopenia,Levovirin™ did not produce any observable clinical pathology.Furthermore, it is especially contemplated that treatment of a viraldisease with Levovirin™ is predominantly based on the modulation of theTh1/Th2 balance towards a Th1 dominated response, and not predominantlybased an a direct antiviral effect. The term “direct antiviral” effector activity as used herein refers to an immediate effect or activity ofa drug on viral assembly or replication. In contrast, a reduction ofviral activity or replication that is at least in part mediated by oneor more components of the immune system is not considered a “directantiviral” effect or activity. Likewise, it should be appreciated that arelative reduction of the Th2 response during a treatment according tothe inventive subject matter may be especially advantageous in diseasesthat are correlated with an increased TU response (e.g., HCV infection).

EXAMPLES

[0027] The following examples illustrate an exemplary synthesis andvarious applications of Levovirin™.

Example 1 Synthesis of Levovirin™

[0028] 1,2,3,5-Tetra-O-acetyl-β-L-ribofuranose (1): To a stirredsolution of L-ribose (50.0 g, 333.33 mmol) in anhydrous methanol (500ml) at room temperature was added freshly prepared dry methanolic HCl(40 ml prepared by bubbling dry HCl gas into methanol at 0° C. to aweight increase of 4 g) via syringe during 15 min period under argonatmosphere. After the addition of methanolic HCL, the reaction mixturewas allowed to stir at room temperature for 3-4 h. Dry pyridine (100 ml)was added and evaporated to dryness under high vacuum below 40° C. Thisprocess was repeated a second time with additional dry pyridine (100ml). The residue was dissolved in dry pyridine (250 ml) and cooled in anice bath to 0° C. under argon atmosphere. To this cold stirred solutionwas added acetic anhydride (100 ml) via a dropping funnel during 15 minperiod. After the addition of acetic anhydride, the reaction was allowedto stir at room temperature under exclusion of moisture for 24 h. Thereaction mixture was evaporated to dryness. The residue was partitionedbetween ethyl acetate (400 ml) and water (400 ml), and extracted inEtOAc. The aqueous layer was extracted again with EtOAc (100 ml). Thecombined EtOAc extract was washed with water (400 ml), saturated NaHCO₃(2×300 ml), water (300 ml) and brine (200 ml). The organic extract wasdried over anhydrous Na₂SO₄, filtered and the filtrate evaporated todryness. The residue was co-evaporated with dry toluene (2×150 ml) athigh vacuum. The dried oily residue (92 g, 95%) was used as such for thefollowing reaction without further characterization.

[0029] The syrup (92 g) from the above reaction was dissolved in glacialacetic acid (300 ml) and treated with acetic anhydride (75 ml) at roomtemperature. The solution was cooled to 0-5° C. in an ice bath underargon atmosphere. Concentrated H₂SO₄ (21 ml) was added slowly during a15 min period. After the addition of H₂SO₄, the reaction mixture wasstirred at room temperature for 14 h and poured on crushed ice (500 g),and stirred until the ice melts. Water (500 ml) was added and extractedwith CHCl₃ (2×300 ml). The chloroform extract was washed with water(3×400 ml), saturated NaHCO₃, (2×300 ml), water (200 ml) and brine (200ml). The washed organic extract was dried over anhydrous MgSO₄, filteredand evaporated to dryness to give an oily residue (99 g). The residuewas co-evaporated with dry toluene (200 ml) and dissolved in ethyl ether(200 ml), which upon cooling at 110° C. for a day produced colorlesscrystals. The crystalline solid was filtered, washed with hexanes: ether(2:1, 50 ml) and dried to give 60.5,g product.

[0030]Methyl-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate(3) andMethyl-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-5-carboxylate(4): A mixture of methyl-1,2,4-triazole-3-carboxylate (25.4 g, 200mmol), 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose (63.66 g, 200 mmol) andbis(p-nitrophenyl)phosphate (1 g) were placed in an RB-flask (500 ml).The flask was placed in a preheated oil bath at 165-175° C. under wateraspirator vacuum with stirring for 25 min. The acetic acid displaced wascollected in an ice-cold trap that is placed between the aspirator andthe RB flask. The flask was removed from the oil bath and allowed tocool. When the temperature of the flask reached roughly 60-70° C., EtOAc(300 ml) and saturated NaHCO₃ (150 ml) were introduced, and extracted inEtOAc. The aqueous layer was extracted again with EtOAc (200 ml). Thecombined EtOAC extract was washed with saturated NaHCO₃ (300 ml), water(300 ml) and brine (200 ml). The organic extract was dried overanhydrous Na₂SO₄, filtered and the filtrate was evaporated to dryness.The residue was dissolved in EtOH (100 ml) and diluted with MeOH (60ml), which on cooling at 0° C. for 12 h produced colorless crystals. Thesolid was filtered, washed with minimum cold EtOH (20 ml) and dried athigh vacuum over solid NaOH to give 60 g (78%). The filtrate wasevaporated to dryness and purified on silica column using ChCl₃->EtOAc(9:1) as the eluent. Two products were isolated from the filtrate: fastmoving product 8.5 g (11%) and slow moving product 5 g (6.5%). The slowmoving product matched with the crystallized product. The fast movingproduct was found to be (4) and obtained as foam. The combined yield of(3) was 65 g (84%).

[0031] 1-β-Ribofuranosyl-1,2,4-triazole-3-carboamide (5):Methyl-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate(62 g, 161 mmol) was placed in a steel bomb and treated with freshlyprepared methanolic ammonia (350 ml, prepared by passing dry HCL gasinto dry methanol at 0° C. until saturation) at 0° C. The steel bomb wasclosed and stirred at room temperature for 18 h. The steel bomb was thencooled to 0° C., opened and the content evaporated to dryness. Theresidue was treated with dry ethanol (100 ml) and evaporated to dryness.The residue obtained was triturated with acetone to give a solid, whichwas filtered and washed with acetone. The solid was dried overnight atroom temperature and dissolved in a hot EtOH (600 ml) and water (10 ml)mixture. The volume of the EtOH solution was reduced to 150 ml byheating and stirring on a hot plate. The hot EtOH solution on coolingprovided colorless crystals, which were filtered, washed with acetoneand dried under vacuum. Further concentration of the filtrate gaveadditional material. The total yield was 35 g (89%).

Example 2 Determination of Cytokine Pattern in Response to Levovirin™and Ribavirin

[0032] Peripheral blood mononuclear cells were isolated from healthydonors by density gradient centrifugation followed by T cell enrichmentusing Lymphokwik (One Lambda, Canoga Park, Calif.). Contaminatingmonocytes were removed by adherence to plastic. Purified T cellswere >99% CD2⁺, <1% HLA-DR⁺, and <5% CD25⁺, and were maintained inRPM1-AP5 (RPMI1640 medium containing 5% autologous plasma, 1% glutamine,1% penicillin/streptomycin and 0.05% 2-mercaptoethanol). For thedetermination of cytokine protein levels, T-cells (0.2*10⁶ in a volumeof 0.2 ml) were activated by the addition of 80 ng of Staphylococcalenterotoxin B (SEB, Sigma. St. Louis, Mich.) and incubated in 96-wellplates in the presence of 0-10 μM of Levovirin™ or Ribavirin for 48 hrsat 37° C. Following activation, supernatants were analyzed forcell-derived cytokine production. The cytokine determination wasperformed using ELISA kits specific for IL-2, IFN-γ and TNF-α(Biosource, Camarillo, Calif.). All ELISA results were expressed aspg/ml. Data shown as percentage of activated control, calculated as theratio of activated T cell cytokines level in the presence of Levovirin™or Ribavirin over the cytokine level of untreated activated T cellstimes 100%. Thus, a zero effect on cytokine levels would give apercentage of activated control value of 100%. FIGS. 3A-C show thesimilarity of dose responses between T cells treated with Ribavirin orLevovirin™ and various Th1 cytokines. Table 1 shows the effect ofRibavirin and Levovirin™ on SEB stimulated T cell expression of the Th1cytokines IL-2, IFN-γ, and TNF-α. The present data clearly suggest thatLevovirin™ offers significant potential for the treatment of thosediseases in which Type 1 cytokines play a critical role. Treatment IL-2IFN-γ TNF-α SEB 100 100 100 SEB + Ribavirin 143 ±18 131 ± 6 124 ± 4SEB + Levovirin ™ 131 ± 12 122 ± 3 144 ± 7

Example 3 Direct Antiviral Activity and Cytotoxicity Assays

[0033] In vitro testing for direct antiviral activity of Levovirin™ andRibavirin against influenza A and B, parainfluenza 1 and 2, andrespiratory syncytial virus were performed as described in Huffman, J.H. et al. Antiviral Chem. and Chemother. 1997, 8: 75-83 and Barnard, D.L. et al. Antiviral Chem. and Chemother 1997, 8: 223-233. Anti-humanimmunodeficiency virus activity was assessed by the National CancerInstitute using a procedure designed to detect agents acting at anystage of the virus reproductive cycle [Weislow, O. W. et al., J. Natl.Cancer Inst. 1989, 81: 577-5861. Anti-hepatitis B (HBV) activity wasmonitored by using an assay as described by Marion et al., Hepatology1987, 7: 724-731. Anti-HIV activity and cytotoxicity for Ribavirin wasdetermined from previous data [McCormick, J. B., Lancet, 1998, II:1367-1369.

[0034] Table 2 shows a comparison of the direct antiviral activity andcytotoxicity of Levovirin™ and Ribavirin in cells infected with variousviruses. Compound Activity HBV HIV INFL. A INFL. B PARA 1 PARA 3 RSVLevovirin ™ Dir. Antiviral >100 >600 >200 >200 >1000 >1000 >1000Cytotoxicity >100 >600 >200 >200 >1000 >1000 >1000 Ribavirin Dir.Antiviral >100 40 6.1 1.9 40 4 5 Cytotoxicity 53 >40 56 >100 >1000 480100

Example 4 Anti-Inflammatory Activities of Levovirin™ in Concanavalin AInduced Hepatitis

[0035] BALB/c mice (6 per group were injected intra-peritoneally with asingle dose of 20 μg (1 mg/kg) of Ribavirin or Levovirin™, or 2001 μlPBS 1 hr prior to intravenous tail vein injection with 0.3 mgConcanavalin A (Con A, Calbiochem, San Diego, Calif.). After 24 hr themice were anesthetized with Penthrane and exanguinated by cardiacpuncture to obtain whole blood. Serum was obtained from clotted bloodand used for determinations of serum alanine aminotransferase (ALT).Serum ALT levels were determined using an enzyme activity assay (Sigma)based on the colorimetric measurement of the products (pyruvic acid andglutamic acid) formed from the catalysis of the substrates, alanaine andcc-ketoglutaric acid. FIG. 4 shows the amounts of serum ALT independence of Ribavirin or Levovirin™, or PBS. Both Ribavirin andLevovirin™ were able to substantially reduce Con A induced serum ALTlevels from about 1900 U/ml to 969 U/ml+/−192 for Ribavirin and 954U/ml+/−179 for Levovirin™.

[0036] Thus, specific embodiments and applications of compounds andmethods of treating a viral infection with Levovirin™ have beendisclosed. It should be apparent, however, to those skilled in the artthat many more modifications besides those already described arepossible without departing from the inventive concepts herein. Theinventive subject matter, therefore, is not to be restricted except inthe spirit of the appended claims. Moreover, in interpreting both thespecification and the claims, all terms should be interpreted in thebroadest possible manner consistent with the context. In particular, theterms “comprises” and “comprising” should be interpreted as referring toelements, components, or steps in a non-exclusive manner, indicatingthat the referenced elements, components, or steps may be present, orutilized, or combined with other elements, components, or steps that arenot expressly referenced.

What is claimed is:
 1. A method of treatment of a viral infection in apatient comprising: administering a compound according to structure 1;wherein structure 1 is


2. The method of claim 1 wherein the viral infection is selected fromthe group consisting of a HIV infection, a HCV infection, and a HBVinfection.
 3. The method of claim 1 wherein the step of administeringincreases a Th1 response relative to a Th2 response in the patient. 4.The method of claim 3 wherein the Th1 response increases.
 5. The methodof claim 4 wherein the increase in the Th1 response comprises a meanpeak increase over an activated control level in IL-2 of at least 70%(by weight).
 6. The method of claim 4 wherein the increase in the Th1response comprises a mean peak increase over an activated control levelin IFN-γ of at least 20% (by weight).
 7. The method of claim 4 whereinthe increase in the Th1 response comprises a mean peak increase over anactivated control level in TNF-α of at least 50% (by weight).
 8. Themethod of claim 4 wherein the increase in the Th1 response comprises amean peak increase over an activated control level in IL-2, IFN-γ, andTNF-α of 42% (by weight), 125% (by weight), and 72% (by weight),respectively.
 9. The method of claim 1 wherein the step of administeringcomprises in vivo administration.
 10. The method of claim 1 wherein thestep of administering comprises oral administration.
 11. The method ofclaim 1 wherein the step of administering comprises injection.
 12. Themethod of claim 1 wherein the step of administering comprisesadministering the compound in a dose between 0.1 mg per kg of bodyweight of the patient and 1.0 mg per kg of body weight of the patient.13. A modulator of an immune response according to structure 1: